Estrogens protect bone mass by inhibiting NAD metabolism in osteoclasts.

Estrogens protect against bone loss by reducing osteoclast number and bone resorption, primarily via direct actions on osteoclast precursors. In these cells, estrogens attenuate RANKL-induced stimulation of mitochondrial complex I, which is crucial for ATP generation through NADH oxidation. NAD promotes redox reactions and activates NAD-dependent enzymes, including the mitochondrial deacetylase SIRT3. However, the contribution of NAD to the skeletal effects of estrogens remains unknown. We show that NAD levels and SIRT3 activity are upregulated by RANKL and inhibited by 17β-estradiol (E) in mouse and human osteoclast precursors. Increasing NAD or the mitochondrial NAD/NADH ratio reverses the inhibitory effects of E on SIRT3 activity and osteoclastogenesis . Deletion of , a key NAD salvage enzyme, reduces NAD and prevents bone loss in ovariectomized mice. Similarly, deletion of in osteoclast precursors mitigates estrogen deficiency-induced bone resorption. These findings indicate that suppression of NAD levels and mitochondrial redox metabolism by estrogens contributes to their anti-resorptive effects via inhibition of SIRT3.